Piperaquine (1,3-bis-[4-(7-chloroquinolyl-4)-piperazin-1]-propane) of Formula 1 is an anti-malarial product that belongs to the bisquinoline class of chemical compounds.

Piperaquine was first synthesized in 1960s (U.S. Pat. No. 3,173,918) and was used in therapy in China and Vietnam. In the last decade it has been object of renewed interest as one of a number of compounds suitable for Artemisinin-based Combination Therapy (ACT). Eurartesim® contains a fixed-ratio drug combination between piperaquine phosphate and dihydroartemisinin to treat uncomplicated P. falciparum malaria. Since piperaquine presents an extremely long half-life, its combination is expected to be effective both in treating clinical malaria and in giving protection from re-infection.
Even if various processes for the synthesis of piperaquine have been described in the literature, they usually involve the use of the key intermediate piperazine quinoline of Formula I, which synthesis is depicted underneath (Scheme 1).

Most of the synthetic routes toward 7-chloro-4-piperazin-1-yl-quinoline that have been devised mainly diverge by the reaction conditions used (i.e., type of solvent, reaction temperature, work-up conditions), purity of this intermediate, rather than by the choice of the reagents themselves. A further common point to most of these syntheses resides in the difficulty to purify this key intermediate of Formula I from side-product or excess of piperazine, resulting in low quality of final piperaquine. Indeed, the main drawback identified when reacting the 4,7-dichloroquinoline with piperazine is the concomitant formation of a dimer of Formula 2.

Such a side-product has been reported to possess some toxicity (Singh T., et al., J. Med. Chem., 1971, 14, 4, 283).
Moreover, lots of existing syntheses of compounds of Formula I require elevated reaction mixture temperatures, and/or toxic solvents, and/or laborious extraction processes, and/or highly diluted reaction conditions, and/or large excess of piperazine which at the end results difficult to completely remove.
The synthesis of 7-chloro-4-(piperazin-1-yl)-quinoline was first disclosed more than 40 years ago (U.S. Pat. No. 3,331,843). The reaction between 4,7-dichloroquinoline and four equivalents of anhydrous piperazine involved the use of phenol as solvent and a laborious work-up to obtain the desired adduct. The latter required a further purification to ensure a high quality final compound presenting a melting point equal to 113.5-114.5° C. corresponding to the one of the pure derivative. Furthermore, the relatively high dilution of the reaction coupled to the nocuous character of the solvent (i.e., phenol) do not render this synthesis really practicable on large scale. Singh T., et al., reported a synthesis of 7-chloro-4-(piperazin-1-yl)-quinoline involving a 10 M excess of piperazine, the reaction being conducted at reflux in ethoxyethanol for 24 h. The work-up involved basification by means of NaOH and a crystallization from cyclohexane (Singh T., et al., J. Med. Chem., 1971, 14, 4, 283). However, the toxicity of this solvent renders this synthesis rather inadequate.
Vennerstrom J. L., et al. a synthesis that involved distillation of the solvent and of the excess of piperazine prior to an extraction with a ternary mixture of ethyl acetate-diethylether-dichloromethane. The crude reaction mixture was then recrystallized from diethylether to get the desired adduct (Vennerstrom J. L., et al., J. Med. Chem. 1998, 41, 4360).
Liu Y., et al., reported lately a further synthesis of 7-chloro-4-(piperazin-1-yl)-quinoline involving highly diluted conditions in N-methyl-2-pyrrolidinone and a work-up by means of dichloromethane to afford the desired compound in 54% yield (Liu Y., et al., Molecules, 2008, 13, 2426).
WO04002960 reported a 65% yielding synthesis of 7-chloro-4-(piperazin-1-yl)-quinoline which made use of ten equivalents of piperazine and high ethanolic dilution conditions, the reaction being conducted in sealed-tube.
In patent application 639MUM2005, the Applicant reported a synthesis implying high methanolic dilution conditions coupled to a work-up necessitating a cooling to 10° C. of the reaction mixture prior to filtrate off the precipitated dimer impurity as well as the excess of piperazine used. The desired adduct was then extracted by means of dichloromethane to give rise to a 98% pure compound. It is noteworthy that even after a filtration step and extraction with dichloromethane, the purity of the compound is only 98%. A higher purity could be obtained by means of a laborious successive crystallization step.
U.S. Ser. No. 11/420,400 (corresponding to patent application US2006/270852) reported a synthesis wherein 7-chloro-4-(piperazin-1-yl)-quinoline was prepared in 95% yield after a long 36 hour period in refluxing i-propyl alcohol in the presence of potassium carbonate.
Sunduru, N., et al., disclosed lately a synthesis wherein 7-chloro-4-(piperazin-1-yl)-quinoline was prepared in 80% yield after 5 hours at reflux in MeOH in the presence of 5 equivalents of piperazine. Surprisingly, the melting point of the obtained adduct (mp=160-162° C.) diverges by more than 50° C. with respect to the one reported elsewhere (Sunduru N., et al., Bioorg. Med. Chem., 2009, 17, 6451).
WO09050734 reported a synthesis wherein 7-chloro-4-(piperazin-1-yl)-quinoline was prepared in 82 to 86% yield from heating to reflux in i-PrOH a 3/1 mixture of piperazine and 4,7-dichloroquinoline in the presence of potassium carbonate. Such a process further involved extraction of the aqueous phase with CH2Cl2 in order to remove the dimer impurity, and subsequent basification of the aqueous phase with liquor ammonia prior to a second extraction with CH2Cl2. After removal of the solvent, the residue was taken-up in hexane to obtain 7-chloro-4-(piperazin-1-yl)-quinoline in 98.56% purity.
Therefore, devising a new synthesis of the precious 7-chloro-4-(piperazin-1-yl)-quinoline which avoids the use toxic reagents and/or solvent, and/or laborious extraction processes, and/or highly diluted reaction conditions, and/or large excess of piperazine which at the end results difficult to completely remove is highly desirable.